Abstract
In primary human melanoma, the membrane-type matrix metalloproteinase, MT3-MMP, is overexpressed in the most aggressive nodular-type tumors. Unlike MT1-MMP and MT2-MMP, which promote cell invasion through basement membranes and collagen type I-rich tissues, the function of MT3-MMP in tumor progression remains unclear. Here, we demonstrate that MT3-MMP inhibits MT1-MMP-driven melanoma cell invasion in three-dimensional collagen, while yielding an altered, yet MT1-MMP-dependent, form of expansive growth behavior that phenocopies the formation of nodular cell colonies. In melanoma cell lines originating from advanced primary or metastatic lesions, endogenous MT3-MMP expression was associated with limited collagen-invasive potential. In the cell lines with highest MT3-MMP expression relative to MT1-MMP, collagen-invasive activity was increased following stable MT3-MMP gene silencing. Consistently, MT3-MMP overexpression in cells derived from less advanced superficially spreading melanoma lesions, or in the MT3-MMP knockdown cells, reduced MT1-MMP-dependent collagen invasion. Rather than altering MT1-MMP transcription, MT3-MMP interacted with MT1-MMP in membrane complexes and reduced its cell surface expression. By contrast, as a potent fibrinolytic enzyme, MT3-MMP induced efficient invasion of the cells in fibrin, a provisional matrix component frequently found at tumor-host tissue interfaces and perivascular spaces of melanoma. Since MT3-MMP was significantly upregulated in biopsies of human melanoma metastases, these results identify MT3-MMP as a matrix-dependent modifier of the invasive tumor cell functions during melanoma progression.
Highlights
Cancer-related mortality is generally associated with the development of metastatic lesions
Membrane-Type-3 Matrix Metalloproteinase (MT3-MMP) is overexpressed in human melanoma metastases and metastatic melanoma cell lines
MT1-MMP is frequently overexpressed in different types of melanoma [4,27], whereas mean MT3-MMP expression is not increased in primary melanoma compared to normal skin (GeneSapiens, www.genesapiens.org; [28])
Summary
Cancer-related mortality is generally associated with the development of metastatic lesions. Comparisons between the gene expression profiles of non-metastatic and metastatic cancers have revealed distinct genetic footprints for each disease state [3] In such analyses, the proteolytic enzyme, membrane-type matrix metalloproteinase 1 (MT1-MMP, MMP14), is often linked to the metastatic disease [4,5] with the protease upregulated in tumor cells as well as surrounding stromal cells [6,7,8,9]. MT1- and MT2-MMP (MMP15) can each drive tumor cell invasion through basement membranes and the collagen type I-rich interstitial stroma [10,15], while MT3-MMP (MMP16) cannot efficiently cleave native collagen type I or confer cells with collagen-invasive ability in vitro or in vivo [15,16,17] When overexpressed, both MT1- and MT3-MMP mediate cell invasion in cross-linked fibrin gel, a provisional form of extracellular matrix commonly deposited within tumor tissues and perivascular spaces in vivo [18]. Unlike wide MT1-MMP expression in different cancers, notable MT3-MMP mRNA levels have been detected in relatively few types of cancer, such as gliomas, hepatocellular carcinoma, gastric cancer and melanoma, where its translation efficiency, protein expression and function remain poorly defined [11,19,20,21,22]
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